B. Abstract and Specific Aims The goals of our center are to 1) elucidate the mechanical biology of T cells 2) use this understanding of T cell mechanical biology to develop novel T cell culture systems'and engineered T cells for improved therapeutics. Adopfive immunotherapy overcomes many obstacles that limit vaccine strategies, by adoptively transferring T cells with controlled anfigenic specificity. In addifion, ex vivo culture of T cells allows for the generation of large numbers of T cells, which is of utmost importance in the face of T cell deficiencies in cancer. A major current challenge in adopfive immunotherapy is to control self-renewal potential of T cell, often referred to in immunology as memory, as it allows the immune system to maintain a higher frequency of T cells specific for pathogens encountered eariier. Another issue is self-renewal capacity in effector populafions such as Th17 CD4 cells that are high effecfive in adoptive immunotherapy models. Hence, by engineering this property into T cells used in adopfive immunotherapy, both the immediate and long-term effects of therapy could be improved. Our NDC hypothesized that the IS integrates chemical and mechanical signals to determine the course of T cell differentiafion. A major goal of our center is thus to improve immunotherapy by controlling the phenotype and funcfion of ex vivo expanded T cells and in scalable numbers. We will focus on immunotherapy of cancers including both leukemias and solid tumors. Besides using adoptive immunotherapy to selectively and directly attack the tumor or tumor stroma, immunotherapy can be used to protect the patient from immunopathology resulting from treatment efforts. During treatment of leukemia by hematopoietic cell transplant (HCT), which aims at reconstituting the recipient with hematopoietic and immune cells post chemotherapy, donor T cells can cause graft-versus-host-disease (GVHD) - a significant source of morbidity and mortality post-HCT. Current approaches to prevent GVHD, which rely on the use of convenfional drugs, and often lead to immunodeficiency, are not safisfactory and new GVHD preventive approaches are cleariy needed. Therefore, within our goal of improving pafient survival and quality of life, we also plan to make use of regulatory T cells (Tregs) to protect pafients from the GVHD toxic effect by modulating Treg funcfion and potency.